Bladder and urethra which are called lower urinary tracts participate in a voiding function and the function is governed by the three types of nerves—sympathetic nerve, parasympathetic nerve and somatic nerve (pudendal nerve). Sympathetic nerve participates in accumulation of urine while parasympathetic nerve participates in urination and pudendal nerve is always active during accumulation of urine showing an action of closing the external urethra sphincter muscle (cf. Rinsho to Kankyu, 71(5):1180, 1994).
There are various diseases which cause the urinary dysfunction and main ones are classified into (1) neurogenic bladder caused by cerebrospinal disease, cerebrovascular accident, diabetes mellitus, peripheral nervous disturbance, etc., (2) organic lower urinary tract obstruction such as benign prostatic hyperplasia and urethral stricture and (3) contraction insufficiency of bladder caused by stress urinary incontinence in adult females, prostatitis, prostatic cancer and anticholinergic agents as well as others which are called LUTS and there are various mechanism for onset of urinary dysfunction depending upon the disease for the cause (cf. Rinsho to Yakubutsu Chiryo, 14(4):304, 1995).
For example, in urinary dysfunction associated with prostatic hyperplasia, the urinary dysfunction is generated by both urethral stricture (mechanical obstruction) caused by compression of enlarged prostate and over-shrinkage (functional obstruction) of smooth muscle of prostate accompanied by an increase in α1 receptors in the enlarged prostate (cf. Rinsho Kagaku, 33(12):1542, 1997).
On the other hand, neurogenic bladder is a general term for abnormal urination caused by disorder of sympathetic nerve, parasympathetic nerve, etc. controlling the action of bladder and urethra but it does not stand for localizing and systematic diseases (cf. “Hyojun Hinyoki Kagaku”, the fifth edition, published in 1998)
Main diseases which cause neurogenic bladder are (1) encephalopathy such as dementia, cerebrovascular disturbance, cerebral wound, encephalitis, brain tumor, multiple sclerosis. Parkinson disease, Shy-Grager syndrome and olivopontocerebellar atrophy, (2) spondylopathy such as spinal cord injury, spinal cord tumor, spondylitis, myelopathy, vascular disease of spinal cord, spinal cord diseases (such as cervical spondylosis, disk herniation and cervical ossification of posterior longitudinal ligament), spina bifida and multiple sclerosis and (3) peripheral nerve disturbance such as diabetes mellitus, operations in pelvic cavity (for radical therapy of uterine cancer and rectum cancer), spinal cord diseases (such as disk herniation, spinal cord stenosis, lumbar separation and spondylolisthesis), Guillan-Barre syndrome, pelvic fracture and cauda equina nerve tumor.
In the urinary dysfunction associated with neurogenic bladder, there are a voiding dysfunction and a strange dysfunction and each of those dysfunction may take place either independently or jointly depending upon phase, site, etc. of the dysfunction. In the voiding dysfunction, symptoms such as retardation of initiation of urination, prolongation of time for urination, intermittent urination, minute urinary stream, etc. appear.
At present, the drugs where the effectiveness in clinic has been confirmed as a therapeutic agent for voiding dysfunction associated with neurogenic bladder in Japan, Europe and U. S. A. are cholinergic drugs only and their effect is to improve the, urinary disturbance by recovering the shrinking force of bladder of a low active type where detrusor reflex is lost.
Since there is no animal model for reflecting the symptom in neurogenic bladder, development of the therapeutic drugs therefor is difficult and, even if a few effective cases were clinically confirmed in some substances other than the above-mentioned cholinergic drugs, no drug which can be competent for practical use an the drug has been obtained yet.
Investigation has been carried out for a possibility for the therapy of neurogenic bladder based upon an improvement of urinary efficiency by a decrease in urethral resistance by administration of an α-receptor antagonists such as phenoxybenzamine and prazosin hydrochloride to adrenalinergic sympathetic nerve which is abundantly distributed in smooth muscle of neck of urinary bladder and urethra of prostate. However, there has been almost no success as a drug which can be competent in clinic.
There has been a demand for developing a therapeutic drug having a new action mechanism which can be, competent in practical use as a therapeutic agent for voiding dysfunction associated with neurogenic bladder.